Compositions and methods of manufacture of compressed powder medicaments

ABSTRACT

Compositions and methods of manufacture for producing a medicament composition capable of absorption through the mucosal tissues of the mouth, pharynx, and esophagus. The present invention relates to such compositions and methods which are useful in administering drugs in a dose-to-effect manner such that sufficient drug is administered to produce precisely a desired effect. The invention also relates to a manufacturing technique that enables a therapeutic agent or drug to be incorporated into a flavored confectionary base and to compress or otherwise attach the solid confectionary mixture onto an appliance or holder. Employing the present invention, the drug may be introduced into the patient&#39;s bloodstream almost as fast as through injection, and much faster than using the oral administration route, while avoiding the negative aspects of both of these methods. The present invention achieves these advantages by incorporating the drug into a compressed powder &#34;candy &#34; matrix. The pH and pKa of the powder matrix can be modified to increase the absorption of the drug through the mucosal tissues.

RELATED APPLICATION

This application is a continuation-in-part application of copendingapplication Ser. No. 729,301, filed May 1, 1985, in the names of theinventors hereof, and entitled "METHODS AND COMPOSITIONS FOR NONINVASIVEADMINISTRATION OF SEDATIVES, ANALGESICS, AND ANESTHETICS," now U.S. Pat.No. 4,671,953 which issued June 9, 1987. That application isincorporated herein by specific reference.

BACKGROUND

1. The Field of the Invention

The present invention relates to compositions and methods of manufactureof compressed powder matrixes for medicaments used in the transmucosaldelivery of the medicaments. More particularly, the present invention isdirected to compositions, and methods and apparatus for producing suchcompositions, for non-invasive administration of precise amounts ofmedicaments through the mucosal tissues of the mouth, pharynx, andesophagus.

2. The Background of the Invention

Recently, numerous advancements have taken place in the field ofpharmacology with respect to the administration of drugs to treatvarious conditions. Despite the tremendous advancements in the field,however, drugs continue to be administered using substantially the sametechniques that have been used for many decades. The vast majority ofpharmaceutical agents continue to be administered either orally or byinjection. Nevertheless, it is frequently found in the art that neitherof these administration routes are effective in all cases, and bothadministration routes suffer from several disadvantages.

Oral administration is probably the most prevalent method ofadministering pharmacological medicaments. The medicament is generallyincorporated into a tablet, capsule, or a liquid base, and thenswallowed. The oral administration modality is often preferred becauseof its convenience. In addition, oral administration is generallynonthreatening, painless, and simple to accomplish for most patients.

Nevertheless, oral administration of drugs suffers from severaldisadvantages. One disadvantage is that pediatric and geriatric patientsfrequently have difficulty swallowing pills, and such patients oftenrefuse to cooperate in swallowing a liquid medication. In addition, formany medicaments, the act of swallowing the medicament increases gastricvolume and the likelihood of nausea and vomiting; this is a particularlydangerous condition for patients prior to anesthesia.

A further problem with oral administration is that the rate ofabsorption of the drug into the bloodstream after swallowing varies frompatient to patient. The absorption of the drug is dependent upon themovement of the drug from the stomach to the small and large intestinesand the effects of secretions from these organs. Anxiety and stress candramatically reduce these movements and secretions, prevent or reducethe final effects of the drug, and delay onset of the drug's effects.

Most significant is the fact that there is normally a substantial delaybetween the time of oral administration and the time that thetherapeutic effect of the drug begins. As mentioned above, the drug mustpass through the gastrointestinal system in order to enter thebloodstream; this typically takes forty-five minutes or longer. Asmentioned above, anxiety and stress often increase this delay.

For many applications, such as premedication before surgery or whereimmediate relief from pain or a serious medical condition or immediateeffectiveness of the drug is required, this delay is unacceptable. Inmodern outpatient units and operating rooms where rapid turnover ofpatients is essential for cost containment, extensive delays in theaction of a drug are simply unacceptable.

An additional disadvantage of oral administration is that many drugs,particularly drugs with central nervous system ("CNS") or cardiovascularaction, are almost immediately metabolized. The veins from the stomachand the small and large intestines pass directly through the liver.Thus, drugs entering the bloodstream must first pass through the liverbefore distribution into the general blood circulation. More than sixtypercent of most drugs (and essentially one hundred percent of certaindrugs) are removed from the patient's bloodstream during this "firstpass" through the liver. The result is that oral administration isimpractical for many drugs, particularly most central nervous system andcardiovascular-acting drugs that are used in critical care situations,as a premedication prior to surgery, or for the induction of anesthesia.

Further, additional stress is placed on the liver as it removes theexcess drug from the bloodstream. This is particularly severe if thecardiovascular or renal vascular treatment has been occurring over anextended period of time. The liver may become overloaded with the drug'smetabolite which then must be excreted in the patient's urine. As aresult, there is an increased risk of hepatic or renal disorders.

Another difficulty encountered in administering drugs orally is thatdosages are prepared or determined for use with an "average" patient.Most drugs have widely varying effects on different patients. Theseeffects depend upon patient habits, subtle genetic differences betweenpatients, blood volumes, age, and numerous other known and unknownfactors. Introducing a bolus of drug orally does not provide the abilityto control the precise dose needed to obtain the desired effect, ratherthe dose is estimated in order to produce an average effect in anaverage patient. The result may be underdosing or overdosing aparticular patient.

Underdosing a patient because of a low susceptibility to the drug failsto evoke the response sought by the physician. Overdosing the patientcan result in dangerous depression of vital body functions, especiallythe heart and lungs. This can cause prolonged respiratory depression(necessitating mechanical ventilation after surgery), cardiacdepression, and cardiac arrest.

In order to avoid some of the disadvantages of oral administration,injection is frequently used. Injecting a drug (generally intravenouslyor intramuscularly), results in rapid entry of the drug into thepatient's bloodstream. In addition, this type of delivery avoids theremoval of large quantities of the drug by the patient's liver. The druginstead becomes rapidly distributed to various portions of the patient'sbody before exposure to the liver.

Most patients, particularly children and geriatric adults, have anaversion to injections. In some patients, this aversion may be sopronounced as to make the use of injections a serious concern. Sinceintense psychological stress can exacerbate a patient's debilitatedcondition, it sometimes becomes undesirable to use injections where thepatient is seriously ill or suffers from a debilitating condition orinjury.

In addition, individual variations in susceptibility in the metabolismof various drugs (particularly drugs with central nervous systemactivity) are even more profound when utilizing the injection route. Inorder to prevent overdosing, it is the practice to inject a patient witha lower than average dose and then supplement the dose with additionalinjections as necessary. This "titration" makes necessary the use ofrepeated injections, which in turn greatly increases stress on thepatient. Again, a precise dose cannot be administered to produce aprecise effect because the patient's response varies widely depending onthe specific characteristics of the specific patient.

One common approach to preparing a patient for surgery is to orallyadminister a sedative or anxiolytic. Although quick onset of sedation oranxiolysis has not always been a critical factor, it is more so now.Changing practices, including the increased use of outpatient units forday surgery and the pressures for cost containment in modern medicine,dictate rapid onset of action and the use of an absolutely ideal dose inorder to avoid increased costs of caring for patients with delayedrecovery secondary to slightly overdosing with anesthesia. Oraladministration of premedication drugs with central nervous systemactivity (which cause a rapid onset of sedation and anxiolysis withoutproducing excessive sedation) is difficult to accomplish.

Some investigators have suggested that it may be possible to administermedication through the buccal mucosa of the cheek pouch or by sublingualadministration. See, copending application Ser. No. 729,301, filed May1, 1985, in the name of the inventors hereof, and entitled "METHODS ANDCOMPOSITIONS FOR NONINVASIVE ADMINISTRATION OF SEDATIVES, ANALGESICS,AND ANESTHETICS." Such administration through the mucosal tissues of themouth, pharynx, and esophagus of therapeutic drugs possesses a distinctusefulness. Administration of drugs by this route does not expose thedrug to the gastric and intestinal digestive juices. In addition, thedrugs largely bypass the liver on the first pass through the body,thereby avoiding additional metabolism and/or inactivation of the drug.

Generally the drugs which are administered by any of the methodsdescribed above have an unpleasant taste. As a result, in order to allowfor buccal or sublingual administration through the oral mucosaltissues, it is also necessary to incorporate the drug into some type ofpleasant tasting mass, such as a "candy" matrix.

In the manufacture of medicated candy products by existing methods, thetherapeutic agent is added to a molten candy mass. The resultant mixtureis then thoroughly mixed to ensure proper distribution of the drugwithin the molten candy mass. The mixture is then poured while stillmolten and allowed to solidify into a semi-solid mass. Alternatively,the hot candy mass may be poured into molds, the size and shape of whichmay be determined as desired.

For effective application of the drug, the final candy product mustcontain the drug uniformly distributed throughout in order to ensureuniform levels of medication. Alternatively, for some applications,varying concentrations within known and controlled ranges may be desiredto vary the rate of drug administration. Difficulties are encountered inattempting to blend solid drugs in a uniform or otherwise carefullycontrolled manner. Many drugs are insoluble, or only partially soluble,in one or more of the ingredients of the hard candy base. Thus, theresultant product is often found to be lacking in uniform distributionof the drug.

In addition, it is often found that when the temperature of the candymass is increased in order to enable a more uniform distribution(generally to a temperature above approximately 230° C.), considerabledecomposition of the drug takes place. While the extent of decompositionmay vary, high temperatures are generally undesirable in the handlingand processing of medications. Thus, the process of formation of thecandy product may itself degrade and/or inactivate the therapeuticagent.

Furthermore, many presently available medicated candy lozenges tend tocrumble when placed in the mouth. As a result, uniform release of thedrug into the mucosal tissues does not take place. Rather, the crumbledlozenge is mostly chewed, and swallowed, and the drug enters thebloodstream through the stomach and intestines as described above. Thus,it will be appreciated that candy lozenges have very definitelimitations for use in the administration of a drug through the oralmucosal tissues. As a result, lozenges have not been used to administerpotent, fast-acting drugs, such as drugs that affect the central nervoussystem, the cardiovascular system, or the renal vascular system.

While the administration of certain drugs through the oral mucosaltissues has shown promise, development of a fully acceptable method forproducing a medication in a desirable form and administering themedication has been elusive. It has not been possible to develop anacceptable candy product for use with most drugs without heating theproduct to the point where degradation will be expected.

It should also be noted that pH conditions within the mouth tend toadversely affect the administration of certain drugs by the mucosaladministration route. It has been found in the art that administrationof drugs through the mucosal tissues occurs best when the drug is in thenon-ionized form. Variations in pH affect drastically the percentage ofthe drug which is non-ionized at a particular point in time. As aresult, the pH conditions within the mouth limit the effectiveness ofcertain drugs administered buccally or sublingually in that thoseconditions cause the drug to exist in the ionized form which is largelyunavailable for transfer across the mucosal tissues.

In view of the foregoing, it would be an important advancement in theart of administering potent, fast-acting drugs, if suitable methods andcompositions provided a precise dosage to a precise effect in everypatient. It would be a related advancement in the art to provide suchmethods and compositions which avoided the disadvantages of overdosing,underdosing, and the immediate metabolism encountered in the "first passeffect," yet did not involve injection by needle into the patient.

It would be a further significant advancement in the art to providemethods and compositions for incorporating drugs (including insolubledrugs) into a soluble matrix without heating the mixture to the pointthat degradation occurs. It would be a related advancement in the art toprovide such a method which provided the capability of uniformlyincorporating insoluble drugs into the soluble matrix. It would beanother advancement to provide methods of controlling pH during mucosaldelivery of a drug such that the drugs exist primarily in thenon-ionized form.

Such compositions and methods of manufacture are disclosed and claimedherein.

BRIEF SUMMARY AND OBJECTS OF THE INVENTION

The present invention relates to compositions and methods of manufacturefor producing a medicament composition for use in administering potent,fast-acting drugs transmucosally. Furthermore, the present inventionrelates to such compositions and methods which are useful inadministering drugs in a dose-to-effect manner such that sufficient drugis administered to produce precisely the desired effect. The inventionalso relates to a manufacturing technique that enables a therapeuticagent to be incorporated into a flavored confectionary base and tocompress or otherwise attach the solid confectionary mixture onto anappliance or holder. In use, the present invention provides for theadministration of drugs through the mucosal tissue of the mouth,pharynx, and esophagus, thereby avoiding the problems of both injectionand oral administration.

Employing the present invention, the drug may be introduced into thepatient's bloodstream almost as fast as through injection, and muchfaster than using the oral administration route, while avoiding thenegative aspects of both methods.

The present invention achieves these advantages by incorporating thedrug into a soluble candy matrix. The soluble candy-drug mixture, in theform of a compressed powder lollipop, can be used to administer drugs ina dose-to-effect manner, or until the precise desired effect isachieved. The lollipop can then be removed from the patient's mouth.

The methods of the present invention also provide for a compressedpowder composition which overcomes many of the limitations previouslyencountered in forming a medicated lozenge. The present inventionteaches the combination of dry powdered ingredients by geometricdilution. That is, the two smallest ingredients by weight are firstthoroughly mixed, then the next smallest ingredient or ingredients byweight equal to the weight of the previous ingredients is added and isthoroughly mixed with the existing mixture. This procedure is repeateduntil all of the components, including the desired therapeutic agents,are fully combined.

After mixing, the mixture is then compressed under high pressure to forman integral candy product. Specific confectionary components arecombined in order for the mixture to form an integral solid mass. Thesecomponents may include, for example, compressible confectioner's sugarand maltodextrin.

This procedure overcomes many of the problems of the prior art.According to the present invention, insoluble drugs can be added to thematrix without the necessity of attempting to dissolve the drug. Inaddition, the high temperatures, which are generally required to form amolten candy matrix and which will cause degradation of the drug, areavoided using the present invention. Therefore, even drugs with meltingpoints below approximately 130° C. to 140° C. or those drugs which canexperience decomposition below their melting points, can be incorporatedinto a soluble matrix.

A further advantage of the present invention is that flavoring problemsare overcome. Flexibility in adding flavors is provided in thatsolubility of the components is not required in order to incorporate anyparticular flavor into the matrix. Thus, flavorings, drugs, and othercomponents (which may be insoluble in liquid form) are easily mixed whenthey exist as a dry powder.

Buffers and other types of pH and pKa control can also be addedsimultaneously in order to provide for maximum drug efficiency. It willbe appreciated that drugs in the non-ionized form are more readilytransported across the mucosal membrane. Therefore, if pH (andcorresponding pKa) conditions can be adjusted to maximize the percentageof non-ionized drug available, the effectiveness of the drug ismaximized.

Various lollipop configurations are also possible employing the presentinvention. For example, layers of drug may be interspersed betweenlayers of candy. Since the present invention teaches the use of solidpowders, any desired type of mold can be used for the compressionformation of the lollipop.

It may also be desirable to incorporate a stick into the candy matrix asthe matrix is being compressed. Alternatively, the stick may be glued tothe candy matrix by a confectioner's glue once the lollipop is formed.The stick provides for easy removal of the lollipop from the mouth ofthe patient once the desired effect has been achieved. This is asubstantial improvement over existing methods of administering drugsthrough the mucosal tissues of the mouth.

The present invention also provides the advantage of controlling thedissolution rate of the composition once it is administered to apatient. This can be accomplished in two ways. First, the dissolutionrate may be modified chemically by including a hydrophobic agent (suchas calcium stearate) to slow dissolution or lactose to enhancedissolution. Dissolution may also be controlled by the extent to whichthe mixture is mechanically compacted.

A drug administered through the oral mucosal tissues from such acompressed powder matrix within the scope of the present invention willquickly enter the patient's bloodstream through the veins which servethese tissues. Appropriate monitoring of the patient's reaction to thedrugs which has an observable or monitorable effect (such as a drugeffecting the central nervous, cardiovascular, or renal vascularsystems) will indicate when the drug has evoked a suitable response. Thelollipop may then be removed, or its rate of consumption may be modifiedin order to maintain the desired effect.

It will be appreciated that the ever present risk of overdosing apatient is substantially minimized through the use of the presentinvention. The rate at which the drug is to be absorbed by the body canbe varied by varying the rate the lollipop dissolves. This can beaccomplished by varying the rigor with which the patient sucks on thelollipop. It can also be accomplished by varying the extent to which thelollipop is compressed during formation or by adding certain agentswhich reduce the solubility of the compressed powder matrix.

According to the present invention, the drug dose is given over a periodof time rather than all at once, and the administration rate can beadjusted if it appears to be necessary. Once a sufficient drug responsehas been achieved, the patient can simply stop sucking on the lollipopor the physician can easily remove the lollipop from the patient'smouth.

It is, therefore, a primary object of the present invention to providemethods of manufacture and compositions in order to accomplish thenon-invasive administration of a drug to a patient in order to rapidlyinduce a desired central nervous system effect.

It is another object of the present invention to provide methods ofmanufacture for forming a drug-containing compressed powder matrix,which methods avoid degradation of the drug, overcome problems relatedto insolubility of the various components in the candy matrix, andprovide a product which is not likely to crumble in the patient's mouth.

It is another object of the present invention to provide compositionswhich allow for precise control of the dosage and effect of the drug tobe administered.

These and other objects and features of the present invention willbecome more fully apparent from the following description and appendedclaims taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a mold for forming the candy-drug matrixalong with an associated ram.

FIG. 2 is a perspective view of one embodiment of a lollipop within thescope of the present invention.

FIG. 3 is an exploded plan view of the embodiment of the lollipop shownin FIG. 2.

FIG. 4 is a perspective view of an alternative embodiment of thelollipop of the present invention.

FIG. 5 is a cutaway plan view of an alternative embodiment of thelollipop of the present invention illustrating one method of attachmentof the stick to the candy matrix.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

1. General Discussion

The present invention is related to methods of manufacture andcompositions which facilitate the transmucosal delivery of a medication.Simply stated, the present invention relates to a lollipop, or similartype of composition, which contains a therapeutic drug. The drug isdelivered to the patient through the mucosal tissues of the mouth,pharynx, and esophagus as the patient sucks on the drug-containinglollipop.

This particular method of delivery overcomes several of the limitationsencountered in the delivery of drugs either orally or by injection. Oneof the primary advantages of the present invention is the ability tointroduce drugs to a patient in a "dose-to-effect" manner. The drug isgiven to the patient until the precisely desired effect is obtained;this is in distinction to prior art methods where a predeterminedquantity of the drug is introduced to the patient. Once the desiredeffect is obtained, the patient or the medical professional simplyremoves the lollipop from the patient's mouth.

The present invention discloses a method of producing a lollipopcontaining one or more therapeutic agents. The present inventionovercomes many of the problems encountered generally in incorporatingdrugs into a confection. For example, the present invention teaches themixing of solid powders at room temperature, as opposed to liquidcomponents at elevated temperatures. The degradation of drugs, whichoften occurs at the elevated temperatures needed to produce a moltencandy mass, is thereby avoided. This facilitates use of drugs havingmelting points in the 130° C.-140° C. range and below, or those drugswhich can experience decomposition below their melting points.

In addition, because solid powders are combined together, constituentswhich may be chemically incompatible when in a heated solution orsuspension can be mixed. In forming medicated confections by knownmethods, severe problems are encountered in that the medication,flavorings, and other components may be insoluble when placed in thesame liquid environment. In addition, problems of chemicalimcompatibility between ingredients is eliminated in the presentinvention.

Once the desired constituents are thoroughly mixed, they are compressedinto a solid mass under high pressure. Typically, compressive forces inthe range from approximately 2,000 Newtons to approximately 5,000Newtons are preferred. As a result, the compressed powdered matrix isheld together by physical means rather than by chemical means. Theextent of the compressive forces can be modified to vary the rate thatthe lollipop will dissolve in a patient's mouth. The greater thecompressive forces that form the mixture, the slower the dissolution ofthe compressed powder matrix in the mouth.

The rate of the dissolution of the lollipop can also be controlledchemically. For example, the rate of dissolution can be reduced addinghydrophobic agents such as calcium stearate. Alternatively, dissolutioncan be increased by adding hydrophilic agents, such as lactose.

According to the present invention, the compressed powder matrix isattached to a holder, such as a stick to form a lollipop. Attaching thecompressed powder matrix to a holder facilitates the administering ofprecise dosages. Once a particular effect is induced, the lollipop canbe withdrawn using the holder as described above. In addition, acompressed solid mass containing a drug having complex disagreeableflavor characteristics require multiple ingredients to be added in orderto provide a significant bulk to overcome the disagreeable flavorcharacteristics; hence, a mechanical support system such as a holder isnecessary.

The attachment of the confection to a holder may be made by compressingthe stick into the powder matrix as the lollipop is being formed.Alternatively, the stick may be glued to the candy matrix byconfectioner's glue or some other appropriate adhesive once the matrixis formed. In the alternative, as will be discussed below, a lollipopmay be assembled immediately prior to use by sliding disks of drug andcandy onto an appropriately configured holder.

It will be appreciated that compression or attachment of thedrug-containing confection onto a holder can facilitate the transmucosalabsorption of a variety of therapeutic agents. Attachment to a holderalso facilitates verifiable transfer of the medication to the patient.The holder provides a convenient point of reference concerningquantities of drug administered at any particular point in time; it iseasy to determine how much of the lollipop has been dissolved in thepatient's mouth.

Localization of effects by agents such as local anesthetic agents,antiplaque agents, local antipruitic agents, local antisecretory agents,and local antifungal agents can also be accomplished according to thepresent invention. Immediate systemic effects from central nervoussystem-acting drugs (such as sedation, anxiolysis, analgesia, amnesia,and anesthesia), cardiovascular-acting agents (such as antihypertensivesand and antianginal drugs), renal vascular-acting agents, and numerousother therapeutic agents can also be accomplished by employing thepresent invention.

Placing a drug dosage onto a holder also facilitates the temporaryremoval of medication for inspection or the reduction of the effect whennecessary. Unlike administration of drugs orally or even sublingually,the present composition can easily be removed to assess the effectinduced at any particular time. When a pill or lozenge is used, removalfrom the patient's mouth at an intermediate stage to assess effect isgenerally impractical, if not impossible.

Compressed powder matrixes attached to a holder can also avoidaspiration of the confection. One major problem with existing lozengesand the like is their tendency to crumble. Once the lozenge crumbles,controlled transmucosal delivery is impossible. In addition, there issome possibility that the patient will choke on the pieces of lozenge.

The present invention provides the capability of providing a goodtasting medication. With many drugs, it has previously been impossibleto provide a good tasting medicine because of the extreme bitterness orother unpleasant taste of many drugs. Using the present invention,favorable taste characteristics can be accomplished by adding variousflavors, sweeteners, and the like to form an ideal mix of products.Since the components are combined as solids, problems associated withcombining flavoring components insoluble in a molten candy mass areavoided.

It is also important to note that it has been found that it is possible,according to the present invention, to use the free acid form of certaindrugs and to buffer those drugs such that extremes in pH, and resultingbad taste, are avoided.

2. Methods of Manufacture

In order to prepare a desirable drug-confection mixture for formationinto a lollipop, it is generally necessary to combine several generaltypes of components. These components include the types of componentsused to prepare typical confections, the desired drug, and otherchemically active ingredients such as buffers and the like. The types ofcomponents involved generally fall into the following categories:

(1) flavorings,

(2) sweeteners,

(3) flavor enhancers,

(4) releasing agents,

(5) buffers, and

(6) one or more therapeutic agents.

As mentioned above, it is preferred that these components each beprovided in a powder, in order to facilitate the mixing and compressionsteps. This provides for convenient combination of the ingredients, evenif they happen to be insoluble or otherwise chemically incompatible. Allthe incipients or inactive ingredients should be on the GRAS list("generally regarded as safe").

A wide range of flavors are available for preparing good tasting anddesirable medications within the scope of the present invention. Theseare required in order to mask the unpleasant taste of the drug.Flavorings may be combined, as desired, to produce a particular flavormix which is compatible with a particular medication. Some of theconfectioner's flavorings which have been used in the context of thepresent invention include artificial vanilla, vanilla cream, mint,cherry, spearmint, grape, coconut, chocolate, menthol, licorice, lemon,and butterscotch.

Each of these flavorings is obtainable in a concentrated powder form.Other flavorings known in the confectionary arts may also be acceptablebecause of the ease of combining the ingredients of the presentinvention. Any number of flavorings may be combined in any desired ratioin order to produce the specific desired taste characteristics requiredfor any particular application. For example, flavor combinations may bevaried in order to be compatible with the flavor characteristics of anyspecific drug.

In order to produce a desirable color for the end product, artificialcolorings may also be added to the composition. The flavorings describedabove are generally a white powder, as are the other major components.Therefore, additional coloring is necessary if a colored end product isdesired. Coloring may also be important as a code to indicate the typeand concentration of drug contained within a particular lollipop. Anytype of color known to be "generally regarded as safe" ("GRAS"), andthus generally used in the confectionary trade, may be used to providecoloring to the product.

In order to provide a good tasting medication, it is necessary to addsweeteners to the composition. Sweeteners which are presently preferredinclude aspartame (NutraSweet®) and compressible confectioner's sugar.Other sweeteners, such as fructose, may also be acceptable for usewithin the scope of the present invention. Again, it is desired that asweetner or combination of sweeteners be obtained which is compatiblewith the drug and the other components such that a good tastingconfection is produced.

Maltodextrin may also be added to provide a better tasting composition.Maltodextrin is generally employed in order to dissipate unpleasantflavors (such as the bitter taste of most drugs) within the composition.In addition, maltodextrin is a highly compressible powder whichfacilitates the formation of the final lollipop product.

For some applications, it may be desirable to add a flavor enhancer tothe composition in order to achieve a good tasting product. Flavorenhancers provide a more pleasant sensation in the patient's mouthduring consumption of the lollipop. Flavor enhancers within the scope ofthe present invention include materials such as ribotide (a nucleotide)and monosodium glutamate ("msg").

In certain medications, it may also be desirable to add a lubricatingagent in order to release the lollipop from the mold. Such agents mayalso provide a certain amount of waterproofing. As mentioned above, therate of dissolution of the lollipop within the patient's mouth may becontrolled chemically, as well as physically, through the extent ofcompression of the composition. These lubricating or releasing agentsmay include substances such as compritol 888, calcium stearate, andsodium stearate. Compritol 888 is a trade name for glyceryl behenate.These agents may enhance dissolution or they may inhibit dissolution asnecessary.

As will be discussed in more detail below, it may also be desirable tobuffer the composition. Buffers provide the ability to place themedication in the mouth in a favorable pH environment for passage acrossthe mucosal tissues of the mouth, pharynx, and esophagus. Buffersincorporated within the composition can be used to affect a pH change inthe salival environment of the mouth in order to favor the existence ofa non-ionized form of the active ingredient or drug which more readilymoves through the mucosal tissues.

In addition, appropriate pH adjustment can aid in producing a morepalatable product with drugs which are either severely acidic (and thussour) or severely basic (and thus bitter). As a result, a buffer systemsuch as citric acid/sodium citrate has been found to be desirable foraddition into the soluble compressed powder matrix.

It will be appreciated that miscellaneous other agents such as lactose,to provide filling and bulk, may also be desirable. Other filling andbulking agents of the type known in the art may also be used.

Added to the confectionary matrix described above will be theappropriate therapeutic agent or drug. As will be discussed in moredetail below, various types of drugs are easily incorporated into thistype of matrix. These include agents which affect the central nervoussystem, the cardiovascular system, or the renal vascular system.

A typical lollipop within the scope of the present invention may includethe following ingredients in order to make 20 dosage forms of 2000milligrams (2 grams) each:

    ______________________________________                                        Ingredient       %           grams                                            ______________________________________                                        citric acid      1%          0.2                                              ribotide         2%          0.4                                              compritol 888    2%          0.4                                              aspartame        2%          0.4                                              vanilla microcaps                                                                              5%          1.0                                              vanilla cream microcaps                                                                        5%          1.0                                              wild cherry microcaps                                                                          3%          0.6                                              peppermint microcaps                                                                           3%          0.6                                                               23%         4.6 grams                                        generic active agent X% (about 0.05%)                                          ##STR1##                                                                      ##STR2##                                                                     ______________________________________                                    

Appropriate changes in flavoring ingredients can be made in this formulato mask or optimize flavor perception in order to achieve ultimateacceptance of the dosage formed by the desired patient group, be itadult, juvenile, pediatric, or neonate.

Each of the components is mixed with the other components in dry form toproduce the compositions of the present invention. It is presentlypreferred to use the method of geometric dilution in mixing the variouscomponents. Using this method, the two smallest ingredients by weight(as a proportion of the final product) are first mixed togetherthoroughly.

When complete mixing has been obtained between those two components, thenext smallest ingredient or ingredients by weight equal to the weight ofthe previous ingredients is added and mixed thoroughly with the existingmixture. This procedure is repeated until all of the components areadded to the mix and mixed thoroughly with all other components.

Geometric dilution provides for complete and thorough mixing of all ofthe components. Using the method described above, there is little chancefor incomplete mixing and uneven distribution of components throughoutthe mix. It will be recognized that this is an advancement over the artin that existing methods may result in incomplete mixing because of theinsolubility of the products.

Once complete mixing is accomplished, the mixture is compressed underrelatively high forces to provide a coherent dosage. Compressive forcesin the range of from approximately 2,000 Newtons to approximately 5,000Newtons are presently preferred, however, any force which is sufficientto compress the ingredients into a coherent, integrated mass could beused.

When employing the present invention, there is no need to heat themixture to a molten mass as has been the practice in the past in formingdrug-containing confections. As a result, heat degradation of the drugcomponent is avoided while good mixing and a uniform product areprovided.

The confectionary mass may be attached to a holder such as a stick orother similar type of holder. The holder may be glued to the confectionby confectioner's glue. Alternatively, the holder may be compressed intothe lollipop by the compressive forces described above.

The figures illustrate several methods of forming the mass ofconfection, as well as methods of attaching the holder. FIG. 1 disclosesa mold block 10. The interior of mold block 10 includes a cavity 12formed in any desired shape so that the ingredients described above canbe compressed sufficiently to form an appropriately shaped dosage. Moldblock 10 may comprise two separate halves 14 and 16. Each half of themold block 10 can be removed in order to remove the confection once itis sufficiently compressed.

Also illustrated in FIG. 1 is ram 18. Ram 18 is configured so that itfits into the cavity 12 and compresses the confection into the base ofcavity 12. Ram 18 may have a hole disposed through its interior in orderto accommodate stick 20. Thus, stick 20 can be placed into the mass ofconfection prior to compression. Ram 18 will then compress theconfection tightly around stick 20. Following compression of theconfection, the stick is securely bound in place.

FIG. 2 discloses an additional embodiment of the confection of thepresent invention. The confection illustrated in FIG. 2 has alternatinglayers of confectionary mass 22 and a drug mass 24. Each alternatingsegment is disk-shaped with the width of the disk being varied accordingto particular needs. Disks 22 and 24 easily slide over stick 26 and seatagainst button 28. Thus, the method of assembly of the confection can beadapted to produce various dosages to fit varying circumstances. Indeed,the patient himself may be capable of assembling an appropriateconfection and varying the content of the medicament to correspond tohis specific needs at any particular time.

FIG. 3 illustrates the method of assembling the embodiment of theinvention as illustrated in FIG. 2. In FIG. 3, the drug disks 24 andconfection disk 22 are spaced apart along stick 26. As can beappreciated from FIG. 3, disks 22 and 24 will slide onto stick 26 andwill seat against button 28. The number of disks and the composition ofthese disks can be easily varied to meet particular patient needs.

Stick 26 may take various shapes. For example, it may be desirable forstick 26 to be oval or triangular in cross section. This would preventdisks 24 and 26 from turning on the stick. In addition, an additionalsleeve (not shown) may be positioned over the exposed portion of thestick with a catch that engages stick 26 so that disks 24 and 26 arelocked in place.

FIG. 4 illustrates a further embodiment of a composition within thescope of the present invention. In FIG. 4, the drug and confection aredivided laterally along the cylindrical mass of the confection. Thus,pieshaped segments of drug 32 and confection 34 are pressed togetheraround stick 30. As illustrated in FIG. 4, drug segments 32 andconfection segments 34 may alternate around a periphery of theconfectionary mass. Alternatively, the spacing of the segments may bevaried to provide other appropriate levels of drug dosage.

FIG. 5 illustrates an alternate method of attachment between theconfectionary mass 36 and the stick 38. Stick 38 illustrated in FIG. 5is constructed with a plurality of protrusions 40. Protrusions 40 extendtoward the exposed portion of the handle such that they prevent theconfection from sliding off the handle. Thus, when the confectionarymass 36 is compressed around stick 38, the mass is securely bound to thestick.

It can be seen, therefore, that the present invention provides a greatdeal of flexibility in the construction of an appropriatedrug-containing confection. The quantity of drug contained in anyconfection can be varied within wide ranges. In addition, variousmethods of attachment of the confection to the stick are available inorder to provide a wide range of flexibility.

3. Control of pH and pKa

It is well known that most drugs are weak acids or weak bases and arepresent in solution in both the non-ionized and ionized forms. It hasbeen found that the non-ionized portion of the drug is usually lipidsoluble and can readily diffuse across the cell membrane. The ionizedportion, conversely, is lipid insoluble and is often unable to penetratethe lipid membrane of the cell. Furthermore, the ionized drug is oftenunable to cross the cell membrane pores because of its positive ornegative charge. As a result, drugs in the ionized form are generallyinefficient in producing a drug effect on the central nervous,cardiovascular, and renal vascular systems.

Whether a drug exists in the ionized or non-ionized form is largelydependent upon its pKa, and correspondingly on the pH of the solution.The present invention provides the unique ability to control the pH ofthe solution and thus the pKa of the drug.

Ingredients of the lollipop or other dosage form can be designed toimpart sufficient change in the pH of the saliva within the mouth suchthat the concentration of the non-ionized drug is increased. When thepercentage of non-ionized drug is increased, transmucosal absorption ofthe drug is correspondingly increased. Therefore, by influencing thesalival pH environment, it is possible to greatly improve the extent andrapidity of actual drug absorption, and therefore, the initial onset ofthe effect of the drug. Adding pH buffering systems (such as citricacid/sodium citrate) into the lollipop dosage can greatly facilitatedelivery of the drug in the non-ionized (lipid soluble) form.

It is often desirable for the pKa to range from approximately 5 toapproximately 8 in order to maximize drug delivery. pKa is thedissociation constant, which is generally defined as the pH at which agiven acid or base is 50% ionized and 50% non-ionized. pKa can becalculated from pH, if the concentrations of the charged and unchargedspecies are known, using the well-known Henderson-Hasselbach equation ifconcentrations of the changed and unchanged species are known. TheHenderson-Hasselbach equation is as follows: ##EQU1## where A-/HA is theratio of the ionized drug form ("A-") to the non-ionized drug form("HA").

The effect on the pKa of varying pH, and thus on the non-ionized drugavailable, is extremely dramatic. For example, methohexital, a potentcentral nervous system-acting drug, has a pKa of 7.9. If at the sametime the general pH of the saliva is about 7.5, these values can then beplaced in the Henderson-Hasselbach equation as follows: ##EQU2## where Xis the ratio of the ionized to the non-ionized drug form. Solving thiscalculation indicates that under typical conditions in the mouth, 60% ofthe methohexital available would exist in the non-ionized form. As wasmentioned above, the non-ionized drug form is the primary form that istransported across the lipid cell membrane.

In the event that the salival pH is buffered down to approximately 6.7,the pKa changes dramatically. This results in a corresponding dramaticchange in the amount of drug available. Under these conditions, 94% ofthe drug available exists in the non-ionized form.

Comparing the pKa produced under the two sets of pH conditions describedabove, it can be seen that dramatic changes occur. Changing the pH from7.5 to 6.7 produces more than a 50% improvement in the concentration ofnon-ionized drug available for delivery across the lipid membrane. Thisresults directly in a dramatic improvement in drug delivery across thecell membranes in the mouth and a corresponding increase in theeffectiveness of the drug administered.

Changes in pH such as those discussed above can be accomplished byincorporating particular buffer systems within the confectioncomposition. One presently preferred buffer system is a citricacid/sodium citrate system; however, other conventional buffers (such asphosphate) may also be used. By using such a buffer, dramatically betterresults may be achieved such that buccal drug absorption is a fullyfeasible and optimal delivery method.

It will be appreciated that an additional advantage of the change of thepH may be that the taste characteristics of the drug can be improved.Drugs which are very high in pH typically are very bitter in taste. Asthe pH drops, the taste becomes less bitter, then salty, and mayeventually become sour. Flavorings can more adequately improve the tastecharacteristics of drugs in the lower pH ranges. As a result, inaddition to improving the drug delivery, buffering pH may also improvethe taste characteristics of the composition.

4. Suitable Therapeutic Agents

In order for the present invention to operate effectively, it isnecessary that the therapeutic agent incorporated within the candymatrix be generally lipophilic or, in the alternative, be capable ofbeing placed in lipophilic form by suitable adjustments in theenvironmental pH or other chemical modification. Thus, it is presentlypreferred that the drug have a pKa in the range of from approximately 6to approximately 8.

It will be appreciated that the present invention may be used with drugshaving a variety of melting points. Even low melting point drugs may beused in the present invention, whereas such drugs were difficult toincorporate into a candy matrix using known methods because of problemssuch as degradation of the drug. For example, methohexital, one of thepresently preferred drugs for use in connection with the presentinvention, has a melting point of approximately 96° C. In order toincorporate methohexital into a hard candy by conventional techniques,the drug would have to be melted and there would be a risk of extensivedecomposition of the active agent.

The present invention has applicability to a variety of drugs affectingthe central nervous system. For example, the present invention mayeasily be utilized in the administration of buterophenones (such asdroperidol and haloperidol); benzodiazepines (such as valium, midazolam,triazolam, oxazolam, and lorazepam); gABA stimulators (such asetomidate); barbiturates (such as pentathol, methohexital, thiamazol,pentobarbital, and hexabarbital); di-isopropylphenols drugs (such asdiprivan); and other central nervous system-acting drugs such aslevodopa. It will be appreciated that other drugs may also be utilizedwithin the scope of the present invention either singly or incombination. It is important, however, that the drug be generallylipophilic, potent, and have the other general characteristics describedherein.

Table 1 lists some of the CNS-acting drugs which are suitable forincorporation into the lollipop of the present invention, as well assome of the characteristics of those drugs.

                                      TABLE 1                                     __________________________________________________________________________    GENERIC DRUG                                                                            DRUG CLASS                                                                             MELTING POINT                                                                           DOSE RANGE                                       __________________________________________________________________________    methohexital                                                                            barbiturate                                                                            92° C.                                                                           10-500 milligrams                                pentobarbital                                                                           barbiturate                                                                            131° C.                                                                          50-200 milligrams                                thiamylal barbiturate                                                                            127° C.                                                                          10-500 milligrams                                thiopental                                                                              barbiturate                                                                            160° C.                                                                          50-500 milligrams                                diazepam  benzodiazepine                                                                         125° C.                                                                          10-40 milligrams                                 lorazepam benzodiazepine                                                                         166° C.                                                                          1-4 milligrams                                   midazolam benzodiazepine                                                                         158° C.                                                                          2-25 milligrams                                  oxazepam  benzodiazepine                                                                         205° C.                                                                          5-40 milligrams                                  triazolam benzodiazepine                                                                         233° C.                                                                          250-1000 milligrams                              droperidol                                                                              buterphenone                                                                           145° C.                                                                          1-10 milligrams                                  haloperidol                                                                             buterophenone      0.5-10 milligrams                                propanidid                                                                              eugenol                                                             etomidate GABA stimulator                                                                        67° C.                                                                           5-60 milligrams                                  disoprofol                                                                              --                                                                  ketamine  phencyclidine                                                                          262° C.                                                                          20-300 milligrams                                diprivan  phenol             5-20 milligrams                                  __________________________________________________________________________

Drugs having effects on the cardiovascular and renal vascular systemsmay also be incorporated into the compressed powder lollipop of thepresent invention. A few examples of such drugs are identified in Table2.

                                      TABLE 2                                     __________________________________________________________________________    GENERIC DRUG                                                                            CLASS/FUNCTION                                                                           MELT P.                                                                             LOLLIPOP DOSE RANGE                                __________________________________________________________________________    Bretylium antiarrhythmic                                                                           97° C.                                                                       50-500 milligrams                                  Capitopril                                                                              ACE inhibitor                                                                            87° C.                                                                       25-75 milligrams                                   Clonidine hypotensive agent                                                                        130° C.                                                                      0.1-0.5 milligrams                                 Enalapril ACE inhibitor                                                                            115° C.                                                                      5-15 milligrams                                    Esmolol   hypotensive/angina                                                                             100-250 milligrams                                 Isosorbide                                                                              angina     70° C.                                                                       2.5-40 milligrams                                  Labetolol hypotensive                                                                              120° C.                                                                      100-400 milligrams                                 Lidocaine antiarrhythmic                                                                           127° C.                                                                      50-250 milligrams                                  Metoprolol                                                                              hypotension                                                                              97° C.                                                                       25-100 milligrams                                  Nadolol   hypotension                                                                              124° C.                                                                      40-160 milligrams                                  Nifedipin hypotensive/angina                                                            vasodilator                                                                              172° C.                                                                      10-40 milligrams                                   Nitroglycerin                                                                           hypotensive/angina                                                                       50° C.                                                                       0.4-1.0 milligram                                  Nitroprusside                                                                           hypotensive                                                                              90° C.                                                                       10-50 milligrams                                   Propranolol                                                                             hypotension/angina                                                                       96° C.                                            Dopamine  renal vascular                                                                           241° C.                                                                      0.5-5 milligrams                                   __________________________________________________________________________

In addition to the foregoing, there are many other drugs which can beincorporated into the compressed powder matrix of the present invention.Exemplary of such drugs are those identified in Table 3.

                  TABLE 3                                                         ______________________________________                                        Antiemetic                                                                    Drug Generic       Dose Range                                                 ______________________________________                                        Benzquinamide      25-100 milligrams                                          Meclizine          25-100 milligrams                                          Metoclopramide     5-20 milligrams                                            Prochlorperazine   5-25 milligrams                                            Trimethobenzamide  100-2500 milligrams                                        ______________________________________                                        Antifungal                                                                    Drug Generic       Dose Range                                                 ______________________________________                                        Clotrimazole       10-20 milligrams                                           Nystatin           100,000-500,000 units                                      ______________________________________                                        Antiparkinson                                                                 Drug Generic       Dose Range                                                 ______________________________________                                        Carbidopa          with levodopa 10-50                                                           milligrams                                                 Levodopa           100-750 milligrams                                         ______________________________________                                        Antisecretory                                                                 Drug Generic       Dose Range                                                 ______________________________________                                        Sucralfate         1-2 grams                                                  ______________________________________                                        Bronchodilator                                                                Drug Generic       Dose Range                                                 ______________________________________                                        Albuterol          0.8-1.6 milligrams                                         Aminophylline      100-500 milligrams                                         Beclomethasone     20-50 micrograms                                           Dyphylline         100-400 milligrams                                         Epinephrine        200-500 micrograms                                         Flunisolide        25-50 micrograms                                           Isoetharine        170-680 micrograms                                         Isoproterenol HCl  60-260 micrograms                                          Metaproterenol     0.65-10 milligrams                                         Oxtriphylline      50-400 milligrams                                          Terbutaline        2.5-10 milligrams                                          Theophylline       50-400 milligrams                                          ______________________________________                                        Migraine                                                                      Drug Generic       Dose Range                                                 ______________________________________                                        Ergotamine         2-4 milligrams                                             Methysergide       2-4 milligrams                                             Propranolol        80-160 milligrams                                          Suloctidil         200-300 milligrams                                         ______________________________________                                        Oxytocic                                                                      Drug Generic       Dose Range                                                 ______________________________________                                        Ergonovine         0.2-0.6 milligrams                                         Oxytocin           5-20 units                                                 ______________________________________                                        Antidiuretic                                                                  Drug Generic       Dose Range                                                 ______________________________________                                        Desmopressin       10-50 micrograms                                           acetate                                                                       Lypressin          7-14 micrograms                                            Vaspressin         2.5-60 units                                               ______________________________________                                        Hypoglycemic                                                                  Drug Generic       Dose Range                                                 ______________________________________                                        Insulin            5-20 units                                                 ______________________________________                                    

When incorporating a drug into a lollipop or candy matrix within thescope of the present invention, the amount of drug used will generallydiffer from the amount used in more traditional injection and oraladministration techniques. Depending upon the lipophilic nature of thedrug, its potency, and its end use, the total concentration of the drugin the typical lollipop may contain up to 50 times the amount of drugwhich would typically be used in an injection. For purposes of example,Tables 1, 2, and 3 set forth presently contemplated ranges of thedosages of certain drugs which could be typically used.

A wide variety of drugs may be used within the scope of the presentinvention. The present invention allows drugs to be incorporated withinthe candy matrix which would otherwise be insoluble, unpleasant tasting,or have other undesirable characteristics. This capability is providedby the compression formation of the candy dosage.

As was mentioned above, methohexital is one presently preferred drug foruse in the lollipop of the present invention. Tests were run in whichmethohexital lollipops were given to six volunteers. The lollipops eachcontained 500 milligrams of methohexital. Each patient experienced thesedative effects of the drug in a matter of minutes after beginning tosuck on the lollipop. These tests indicated that the lollipop of thepresent invention is effective in administering methohexital in adose-to-effect manner.

Using the methohexital lollipop described above, it was possible toproduce either mild or heavy sedation or induce anesthesia. By removingthe lollipop when the ideal degree of sedation was achieved, it waspossible to gradually increase sedation to the desired level.

In addition, the results show that the use of oral transmucosalmethohexital significantly decreases the drug dosage required to produceoptimal sedation. The dosage was reduced from between 25 and 30 mg/kgwhen methohexital is administered rectally to between 6 and 8 mg/kgmethohexital is given by way of the lollipop.

In summary, it will be appreciated that a wide variety of drugs can beused within the scope of the present invention. At the same time,several benefits are provided. Efficient delivery of the drug isfacilitated while at the same time drug degradation is avoided. The drugcan also be administered in a dose to effect manner so that the drugeffect produced is precisely controlled.

5. Examples of the Present Invention

The following examples are given to illustrate various embodiments whichhave been made or may be made in accordance with the present invention.These examples are given by way of example only, and it is to beunderstood that the following examples are not comprehensive orexhaustive of the many types of embodiments of the present inventionwhich can be prepared in accordance with the present invention.

EXAMPLE 1

In this example, methohexital was incorporated into a compressed dosageform. Methohexital is a known potent lipophilic drug useful as ananxiolytic, sedative and for anesthetizing a patient. Its high potencyand lipophilicity makes it an excellent drug for transmucosaladministration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredientsas follows:

    ______________________________________                                        Ingredient         %       grams                                              ______________________________________                                        citric acid        1%      0.2                                                ribotide           2%      0.4                                                compritol 888      2%      0.4                                                aspartame          2%      0.4                                                vanilla microcaps  5%      1.0                                                vanilla cream microcaps                                                                          5%      1.0                                                wild cherry microcaps                                                                            3%      0.6                                                peppermint microcaps                                                                             3%      0.6                                                compressible sugar 20%     4.0                                                methohexital sodium                                                                              25%     5.0                                                maltodextrin       32%     6.4                                                                   100%    20                                                 ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultedin the preparation of 10 oral transmucosal dosage forms, each containing0.5 grams of methohexital.

EXAMPLE 2

In this example, triazolam was incorporated into a compressed dosageform. Triazolam is a known potent lipophilic drug useful as ananxiolytic, amnestic, and for sedating a patient. Its high potency andlipophilicity makes it an excellent drug for transmucosal administrationin accordance with the present invention.

A suitable mixture was prepared by combining the following ingredientsas follows:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        triazolam          0.05%     0.01                                             citric acid        1%        0.2                                              Ribotide           2%        0.4                                              Compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              compressible sugar 25.65%    5.13                                             maltodextrin       50.3%     10.26                                                               100%      20.0                                             ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultedin the preparation of 10 oral transmucosal dosage forms, each containing1.0 milligrams of triazolam.

EXAMPLE 3

In this example, oxazepam was incorporated into a compressed dosageform. Oxazepam is a known potent lipophilic drug useful as ananxiolytic, an amnestic, and for sedating a patient. Its high potencyand lipophilicity makes it an excellent drug for transmucosaladministration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredientsas follows:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        citric acid        1%        0.2                                              oxazepam           1.5%      0.3                                              ribotide           2%        0.4                                              compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              compressible sugar 25.17%    5.03                                             maltodextrin       50.33%    10.07                                                               100%      20                                               ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultedin the preparation of 10 oral transmucosal dosage forms, each containing30 milligrams of oxazepam.

EXAMPLE 4

In this example, lorazepam is incorporated into a compressed dosageform. Lorazepam is a known potent lipophilic drug useful as ananxiolytic, an amnestic, and for sedating a patient. Its high potencyand lipophilicity makes it an excellent drug for transmucosaladministration in accordance with the present invention.

A suitable mixture is prepared by combining the following ingredients asfollows:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Lorazepam          0.2%      0.04                                             citric acid        1%        0.2                                              Ribotide           2%        0.4                                              Compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              compressible sugar 25.6%     5.12                                             maltodextrin       51.2%     10.24                                                               100%      20                                               ______________________________________                                    

The ingredients are combined in a mixer in such a fashion as to ensure auniform distribution of all ingredients within the mixture. Aliquots of2 grams each are then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultsin the preparation of 10 oral transmucosal dosage forms, each containing4.0 milligrams of lorazepam.

EXAMPLE 5

In this example, etomidate was incorporated into a compressed dosageform. Etomidate is a known potent lipophilic drug useful as ananxiolytic, sedative and for anesthetizing a patient. Its high potencyand lipophilicity makes it an excellent drug for transmucosaladministration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredientsas follows:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        etomidate          1%        0.2                                              citric acid        1%        0.2                                              ribotide           2%        0.4                                              compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              compressible sugar 25.3%     5.06                                             maltodextrin       50.7      10.14                                                               100%      20                                               ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultedin the preparation of 10 oral transmucosal dosage forms, each containing20 milligrams of etomidate.

EXAMPLE 6

In this example, thiamylal was incorporated into a compressed dosageform. Thiamylal is a known potent lipophilic drug useful as ananxiolytic, sedative and for anesthetizing a patient. Its high potencyand lipophilicity makes it an excellent drug for transmucosaladministration in accordance with the present invention.

A suitable mixture was prepared by combining the following ingredientsas follows:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        citric acid        1%        0.2                                              ribotide           2%        0.4                                              compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              thiamylal sodium   25%       5.0                                              maltodextrin       32%       6.4                                              compressible sugar 20%       4.0                                                                 100%      20                                               ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The procedure resultedin the preparation of 10 oral transmucosal dosage forms, each containing0.5 grams of thiamylal.

EXAMPLE 7

The same procedure described with reference to Example 1 is used butlevadopa is used in place of methohexital. Levadopa is used as necessaryto treat Parkinson's Disease.

EXAMPLE 8

In this example, isosorbide dinitrate was incorporated into a compresseddosage form. In order to make 20 dosage forms of 2000 milligrams (2grams), each containing 20 milligrams of isosorbide dinitrate (for atotal formula weight of 20 grams), the following ingredients werecombined:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        isosorbide dinitrate                                                                             1%        0.2                                              citric acid        1%        0.2                                              ribotide           2%        0.4                                              compritol 888      2%        0.4                                              aspartame          2%        0.4                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              wild cherry microcaps                                                                            3%        0.6                                              peppermint microcaps                                                                             3%        0.6                                              compressible sugar 25.3%     5.06                                             maltodextrin       50.7%     10.14                                                               100%      20                                               ______________________________________                                    

The ingredients were combined in a mixer in such a fashion as to ensurea uniform distribution of all ingredients within the mixture. Aliquotsof 2 grams each were then hydraulically compressed around a commerciallyavailable wax-coated compressed paper holder, using a force sufficientto provide a final volume of 2 cubic centimeters. The foregoingprocedure resulted in the preparation of 20 oral transmucosal dosageforms, each containing 10 milligrams of isosorbide dinitrate.

EXAMPLE 9

In this example, the same procedure as that described in Example 8 isfollowed except captopril is substituted for isosorbide dinitrate.

EXAMPLE 10

In this example, the same procedure as that described in Example 8 isfollowed except nifedipine was substituted for isosorbide dinitrate.

EXAMPLE 11

In this example, the same procedure as that described in Example 8 isfollowed except clonidine is substituted for isosorbide dinitrate.

EXAMPLE 12

In this example, the same procedure as that described in Example 8 isfollowed except esmolol is substituted for isosorbide dinitrate.

EXAMPLE 13

In this example, nitroglycerin was selected for incorporation into acompressed dosage form. Nitroglycerin is a potent lipophilic drug usefulto control angina and blood pressure in perioperative hypertension,especially when associated with cardiovascular procedures and to producecontrolled hypertension during surgical procedures.

The high potency and lipophilicity of the nitroglycerin make it anexcellent drug for transmucosal administration in accordance with thepresent invention. A suitable mixture is prepared by combining 16milligrams of nitroglycerin; 400 milligrams citric acid; 400 milligramscalcium stearate; 17.7 grams compressible sugar; 17.7 grams ofmaltodextrin; 600 milligrams peppermint microcaps; 1.2 grams cherrymicrocaps and 2 grams vanilla microcaps. Aliquots of 2000 milligramseach are then hydraulically compressed around a commercially availablewax-coated compressed paper holder, using a force sufficient to providea final volume of 2 cubic centimeters. The foregoing procedure resultsin the preparation of 20 lollipops, each containing 0.8 milligrams ofnitroglycerin.

EXAMPLE 14

To make 10 dosage forms of 2000 milligrams (2 grams), each containing 10mg of nifedipine (for a total formula weight of 20 grams) the followingingredients were combined:

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Ribotide           1%        0.2                                              Compritol 888      5%        1.0                                              vanilla microcaps  5%        1.0                                              vanilla cream microcaps                                                                          5%        1.0                                              Nifedipine         19.0%     3.8                                              Compressible sugar 21.7%     4.34                                             Dextromaltrin      43.3%     8.66                                                                100%      20 grams                                         ______________________________________                                    

Appropriate changes in flavoring ingredients can be made in this formulato mask or optimize flavor perception in order to achieve ultimateacceptance of the dosage form by the desired patient group, be it adult,juvenile, pediatric, or neonate.

EXAMPLE 15

In this example, ergotamine is selected for incorporation into acompressed dosage form. Ergotamine is a potent lipophilic drug usefulfor relieving the pain associated with migraines. Its high potency andlipophilicity make it an excellent drug for transmucosal administrationin accordance with the present invention.

A suitable matrix is prepared by combining 40 milligrams of ergotamine;5.22 grams compressible sugar; 10.44 grams maltodextrin; 400 milligramsof Aspartame; 200 milligrams natural mint; 600 milligrams cherry; 1.0gram artificial vanilla; 1.0 artifical vanilla cream; 300 milligramsribotide; and 800 milligrams Compritol 888. Alloquats of 2000 milligramseach are then hydraulically compressed around a commercially availablewax-coated compressed paper holder, using a force sufficient to providea final volume of 2 cubic centimeters. The foregoing procedure resultsin the preparation of 10 lollipops, each containing 4 milligrams ofergotamine.

EXAMPLE 16

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of pain associated with oral candiasis is madeaccording to the procedure of Example 15, except that the ingredientsare combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Clotrimazole       1.0%      0.2                                              Natural mint       1.0%      0.2                                              Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificil vanilla cream                                                                          5.0%      1.0                                              Compressed sugar   25.83%    5.17                                             Maltodextrin       51.67%    10.33                                            ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 20 milligrams of clotrimazole.

EXAMPLE 17

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of pain associated with symptoms of esophagitisis made according to the procedure of Example 15, except that theingredients are combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Natural mint       1.0%      0.2                                              Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificial vanilla cream                                                                         5.0%      1.0                                              Compressed sugar   9.5%      1.9                                              Maltodextrin       19.0%     3.8                                              Al. sucrose sulfate                                                                              50.0%     10.0                                             ______________________________________                                    

The foreoing procedure results in the preparation of 10 lollipops, eachcontaining 1 gram of aluminum sucrose sulfate.

EXAMPLE 18

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of pain associated with respiratory distress ismade according to the procedure of Example 15, except that theingredients are combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Natural mint       1.0%      0.2                                              Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificial vanilla cream                                                                         5.0%      1.0                                              Oxtriphylline      10.0%     2.0                                              Compressed sugar   22.83%    4.57                                             Maltodextrin       45.67%    9.13                                             ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 200 milligrams of oxtriphylline.

EXAMPLE 19

A drug-containing lollipop within the scope of the present invention tobe used in the treatment associated with patients experiencing nauseaand vomiting is made according to the procedure of Example 15, exceptthat the ingredients are combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Natural mint       1.0%      0.2                                              Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Meclizine          2.5%      0.5                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificial vanilla cream                                                                         5.0%      1.0                                              Compressed sugar   25.33%    5.07                                             Maltodextrin       50.67%    10.13                                            ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 50 milligrams of meclizine.

EXAMPLE 20

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of the symptoms associated with polyuria ismade according to the procedure of Example 15, except that theingredients are combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Desmopressin       0.001     0.0002                                           Natural mint       1.0%      0.2                                              Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificial vanilla cream                                                                         5.0%      1.0                                              Compressed sugar   26.17%    5.234                                            Maltodextrin       52.33%    10.47                                            ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 20 micrograms of desmopressin.

EXAMPLE 21

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of the symptoms of Parkinson's Disease is madeaccording to the procedure of Example 15, except that the ingredientsare combined in the following amounts.

    ______________________________________                                        Ingredient         %         grams                                            ______________________________________                                        Natural mint       1.0%      0.2                                              Carbidopa          1.25%     0.25                                             Ribotide           1.5%      0.3                                              Aspartame          2.0%      0.4                                              Wild cherry        3.0%      0.6                                              Compritol 888      4.0%      0.8                                              Artificial vanilla 5.0%      1.0                                              Artificial vanilla cream                                                                         5.0%      1.0                                              Levodopa           12.5%     2.5                                              Compressed sugar   21.58%    4.32                                             Maltodextrin       43.17%    8.63                                             ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 25 milligrams of carbidopa and 250 milligrams of levodopa.

EXAMPLE 22

A drug-containing lollipop within the scope of the present invention tobe used to induce labor or reduce postpartum hemorrhage is madeaccording to the procedure of Example 15, except that the ingredientsare combined in the following amounts.

    ______________________________________                                        Ingredient         %       grams                                              ______________________________________                                        Oxytocin           0.001%  0.0002                                             Natural mint       1.0%    0.2                                                Ribotide           1.5%    0.3                                                Aspartame          2.0%    0.4                                                Wild cherry        3.0%    0.6                                                Compritol 888      4.0%    0.8                                                Artificial vanilla 5.0%    1.0                                                Artificial vanilla cream                                                                         5.0%    1.0                                                Compressed sugar   26.17%  5.234                                              Maltodextrin       52.33%  10.466                                             ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining 20 micrograms of oxytocin.

EXAMPLE 23

A drug-containing lollipop within the scope of the present invention tobe used in the treatment of the symptoms of diabetes is made accordingto the procedure of Example 15, except that the ingredients are combinedin the following amounts.

    ______________________________________                                        Ingredient         %       grams                                              ______________________________________                                        Insulin            0.05%   0.01                                               Natural mint       1.0%    0.2                                                Ribotide           1.5%    0.3                                                Aspartame          2.0%    0.4                                                Wild cherry        3.0%    0.6                                                Compritol 888      4.0%    0.8                                                Artificial vanilla 5.0%    1.0                                                Artificial vanilla cream                                                                         5.0%    1.0                                                Compressed sugar   26.15%  5.23                                               Maltodextrin       52.3%   10.46                                              ______________________________________                                    

The foregoing procedure results in the preparation of 10 lollipops, eachcontaining the equivalent of 30 units of insulin.

6. Summary

In summary, it can be seen that the present invention accomplishes theobjects set forth above. The present invention provides compositions andmethods of manufacture for administering a drug in a precise dose inorder to obtain a rapid effect. In addition, the present inventionprovides methods for forming a drug containing candy matrix having thefollowing attributes:

(1) drugs having relatively low melting points can be used withoutdegrading the drug;

(2) disagreeable flavor characteristics can be masked;

(3) insoluble ingredients can be used;

(4) chemically incompatible ingredients can be used;

(5) buffers can be added to optimize the ratio of ionized and nonionizeddrug form;

(6) chemical agents to modify the dissolution characteristics of thedrug can be added;

(7) dissolution characteristics can be modified mechanically by changingthe compressive forces used to form the lollipop;

(8) stratification of active ingredients can be accomplished; and

(9) the dosage can be modified by utilizing an assembly of dosage unitsonto a holder.

The present invention, therefore, provides the ability to provideprecise control over the dosage and effect of the drug. This is obtainedby transmucosal administration by sucking on a lollipop containing thedrug. As a result, the precise dosage and effect can be obtained.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrativeand not restrictive. The scope of the invention is, therefore, indicatedby the appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed and desired to be secured by United States LettersPatent is:
 1. A method for producing a drug-containing lollipop for usein transmucosal delivery of the drug to a patient, the method comprisingthe steps of:(a) obtaining a pharmacologically effective dose of thedrug in a substantially powdered form, the drug being capable ofabsorption through mucosal tissues of the mouth, pharynx, and esophagus;(b) obtaining a soluble carbohydrate material capable of forming acompressible confectionary matrix and capable of dissolving in the mouthof the patient; (c) mixing the drug and the carbohydrate material at atemperature below the melting points of the drug and the carbohydratematerial to form a drug-containing matrix such that the drug isdispersed substantially throughout the matrix, the drug-containingmatrix being capable of releasing the drug for absorption through themucosal tissues upon dissolution of the matrix in the mouth of thepatient; (d) compressing the drug-containing matrix in a mold to form anintegral mass such that, when the integral mass dissolves in the mouthof the patient, the drug is released for absorption through the mucosaltissues; and (e) incorporating a holder as part of the integral mass inorder to form the drug-containing lollipop.
 2. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 1 wherein a buffer is added to thedrug-containing matrix.
 3. A method for producing a drug-containinglollipop for use in transmucosal delivery of the drug to a patient asdefined in claim 2 wherein the buffer modifies the pKa of the drug suchthat, when the integral mass is dissolved, a majority of the drugremains non-ionized in order to facilitate transmucosal absorption ofthe drug.
 4. A method for producing a drug-containing lollipop for usein transmucosal delivery of the drug to a patient as defined in claim 3wherein the buffer is citric acid/sodium citrate.
 5. A method forproducing a drug-containing lollipop for use in transmucosal delivery ofthe drug to a patient as defined in claim 1 wherein the drug hassufficient lipophilic properties such that the drug can be absorbedthrough the mucosal tissue.
 6. A drug-containing lollipop for use intransmucosal delivery of the drug to a patient comprising:a soluble,compressible carbohydrate material; a pharmacologically effective doseof a drug in a substantially powdered form, the drug being capable ofabsorption through mucosal tissues of the mouth, pharnyx, and esophagusand being dispersed substantially uniformly throughout the carbohydratematerial at a temperature below the melting points of the drug and thecarbohydrate material and compressed with the carbohydrate material intoa solid integral mass which is capable of dissolving in the mouth of thepatient so that the drug is released for absorption through mucosaltissues of the mouth, pharnyx, and esophagus upon dissolution of theintegral mass in the mouth of the patient; holder means secured to theintegral mass so as to form a drug-containing lollipop, the holder meansbeing configured so as to permit convenient insertion and removal of thedrug-containing integral mass into and out of the mouth of a patient. 7.A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 1wherein the holder is incorporated into the integral mass by compressionof the drug-containing matrix around the holder during compressing step(d).
 8. A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 1wherein the holder is incorporated as part of the integral mass byaffixing the holder to the integral mass after compressing step (d). 9.A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 1wherein the soluble carbohydrate material in the drug-containing matrixincludes compressible confectionary sugar.
 10. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 9 wherein the drug-containing matrixincludes a lubricating agent such that the integral mass can be releasedfrom the mold after compressing step (d).
 11. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 1 wherein the drug-containing matrixincludes at least one flavor enhancer.
 12. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 1 wherein the drug-containing matrixincludes maltodextrin in order to aid in dissipating any unpleasantflavors of the drug.
 13. A method for producing a drug-containinglollipop for use in transmucosal delivery of the drug to a patient asdefined in claim 1 wherein a substantially water-insoluble component isadded to the drug-containing matrix such that the dissolution of theintegral mass in the mouth of the patient is made slower by thesubstantially water-insoluble component in the drug-containing matrix.14. A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 1wherein the confectionary mixture is compressed with forces in the rangeof from about 2000 newtons to about 5000 newtons.
 15. A method forproducing a drug-containing lollipop for use in transmucosal delivery ofthe drug to a patient as defined in claim 1 wherein the drug ismethohexital.
 16. A method for producing a drug-containing lollipop foruse in transmucosal delivery of the drug to a patient as defined inclaim 1 wherein the drug is selected from the group consisting oftriazolan, oxazepam, lorazepam, etomidate, and thiamylal.
 17. A methodfor producing a drug-containing lollipop for use in transmucosaldelivery of the drug to a patient as defined in claim 1 wherein the drugis nitroglycerin.
 18. A method for producing a drug-containing lollipopfor use in transmucosal delivery of the drug to a patient in adose-to-effect manner, the method comprising the steps of:(a) obtaininga pharmacologically effective dose of the drug in a substantiallypowdered lipophilic form capable of absorption through mucosal tissuesof the mouth, pharnyx, and esophagus; (b) obtaining a solublecarbohydrate material capable of forming a compressible confectionarymatrix and capable of dissolving in the mouth of the patient; (c)obtaining a buffer capable of modifying the pKa of the drug such that amajority of the drug remains non-ionized in order to facilitatetransmucosal absorption of the drug; (d) mixing the drug, the solublecarbohydrate material, and the buffer at a temperature below the meltingpoints of the drug and the carbohydrate material to form a soliddrug-containing matrix such that the drug is dispersed substantiallythroughout the matrix, the drug-containing matrix being capable ofreleasing the drug for absorption through the mucosal tissues upondissolution of the matrix in the mouth of the patient; (e) compressingthe drug-containing matrix in a mold to form an integral mass such thatwhen the integral mass dissolves in the mouth of the patient, the drugis released for absorption through the mucosal tissues such that thedrug is administered in a dose-to-effect manner; and (f) incorporating aholder as part of the integral mass in order to form the drug-containinglollipop.
 19. A method for producing a drug-containing lollipop for usein transmucosal delivery of the drug to a patient as defined in claim 18wherein the holder is incorporated into the integral mass by compressionof the drug-containing matrix around the holder during compressing step(e).
 20. A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 18wherein the holder is incorporated as part of the integral mass byaffixing the holder to the integral mass after compressing step (e). 21.A method for producing a drug-containing matrix for use in transmucosaldelivery of the drug to a patient as defined in claim 18 wherein thedrug-containing mixture includes maltodextrin in order to aid indissipating any unpleasant flavors of the drug.
 22. A method forproducing a drug-containing matrix for use in transmucosal delivery ofthe drug to a patient as defined in claim 18 wherein the buffercomprises citric acid/sodium citrate.
 23. A method for producing adrug-containing matrix for use in transmucosal delivery of the drug to apatient as defined in claim 18 wherein the drug-containing matrixincludes compressible sugar.
 24. A method for producing adrug-containing matrix for use in transmucosal delivery of the drug to apatient as defined in claim 18 wherein the drug-containing matrixincludes a flavoring ingredient.
 25. A method for producing adrug-containing matrix for use in transmucosal delivery of the drug to apatient as defined in claim 18 wherein the confectionary mixture iscompressed with forces in the range of from about 2000 newtons to about5000 newtons.
 26. A method for producing a drug-containing matrix foruse in transmucosal delivery of the drug to a patient as defined inclaim 18 wherein the drug is methohexital.
 27. A method for producing adrug-containing matrix for use in transmucosal delivery of the drug to apatient as defined in claim 18 wherein the drug is selected from thegroup consisting of triazolan, oxazepam, lorazepam, etomidate andthiamylal.
 28. A method for producing a drug-containing matrix for usein transmucosal delivery of the drug to a patient as defined in claim 18wherein the drug is selected from the group consisting of isosorbidedinitrate, captopril, nifedipine, clonidine, and esimolol.
 29. A methodfor producing a drug-containing matrix for use in transmucosal deliveryof the drug to a patient as defined in claim 18 wherein the drug isnitroglycerin.
 30. A method for producing a drug-containing matrix foruse in transmucosal delivery of the drug to a patient as defined inclaim 18 wherein the drug is a potent, fast-acting drug.
 31. A methodfor producing a drug-containing matrix for use in transmucosal deliveryof the drug to a patient as defined in claim 30 wherein the drug haseffects on the central nervous system of the patient.
 32. A method forproducing a drug-containing matrix for use in transmucosal delivery ofthe drug to a patient as defined in claim 30 wherein the drug haseffects on the cardiovascular system of the patient.
 33. A method forproducing a drug-containing matrix for use in transmucosal delivery ofthe drug to a patient as defined in claim 30 wherein the drug haseffects in the renal vascular system of the patient.
 34. A method forproducing a drug-containing matrix for use in transmucosal delivery ofthe drug to a patient as defined in claim 20 wherein the materials inthe drug-containing matrix includes a lubricating agent such that theintegral mass can be released from the mold after compressing step (d).35. A method for producing a drug-containing matrix for use intransmucosal delivery of the drug to a patient as defined in claim 34wherein the lubricating agent comprises glyceryl behenate.
 36. A methodfor producing a drug-containing matrix for use in transmucosal deliveryof the drug to a patient as defined in claim 34 wherein the releasingagent is a substantially water-insoluble component such that thedissolution of the integral mass in the mouth of the patient is madeslower by the substantially water-insoluble component in thedrug-containing matrix.
 37. A drug-containing lollipop for use intransmucosal delivery of the drug to a patient, said compositioncomprising:a soluble, compressible, substantially powdered carbohydratematerial; a pharmacologically effective dose of a lipophilic drug in asubstantially powdered form, the drug being capable of absorptionthrough mucosal tissues of the mouth, pharnyx, and esophagus and beingdispersed substantially uniformly throughout the carbohydrate materialat a temperature below the melting points of the drug and thecarbohydrate material and compressed with the carbohydrate material intoa solid integral mass which is capable of dissolving in the mouth of thepatient so that the drug is released for absorption through mucosaltissues of the mouth, pharnyx, and esophagus upon dissolution of theintegral mass in the mouth of the patient; a buffer which is alsodispersed substantially uniformly throughout the integral mass, thebuffer being capable of modifying the pKa of the drug such that amajority of the drug remains non-ionized in order to facilitatetransmucosal absorption of the drug; and holder means secured to theintegral mass so as to form a drug-containing lollipop, the holder meansbeing configured so as to permit convenient insertion and removal of thedrug-containing integral mass into and out of the mouth of a patient.38. A drug-containing lollipop for use in transmucosal delivery of thedrug to a patient as defined in claim 37, wherein the buffer is citricacid/sodium citrate.
 39. A drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 37,wherein the soluble carbohydrate material in the drug-containingintegral mass includes compressible confectionary sugar.
 40. Adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 39, wherein the drug-containing integralmass further includes a lubricating agent dispersed substantiallyuniformly throughout the integral mass in order to aid in themanufacture of the drug-containing lollipop.
 41. A drug-containinglollipop for use in transmucosal delivery of the drug to a patient asdefined in claim 39, wherein the drug-containing integral mass furtherincludes maltodextrin dispersed substantially uniformly throughout theintegral mass in order to aid in dissipating any unpleasant flavors ofthe drug in the integral mass.
 42. A drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 41,wherein the drug-containing integral mass further comprises at least oneflavor enhancer dispersed substantially uniformly throughout theintegral mass.
 43. A drug-containing lollipop for use in transmucosaldelivery of the drug to a patient as defined in claim 37, wherein thedrug-containing integral mass further comprises a substantiallywater-insoluble component dispersed substantially uniformly throughoutthe integral mass in order to slow the dissolution of the integral massin the mouth of the patient.
 44. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 18 further comprising the step of mixingat least one flavoring with the drug-containing matrix.
 45. A method forproducing a drug-containing lollipop for use in transmucosal delivery ofthe drug to a patient as defined in claim 18 further comprising the stepof mixing at least one flavor enhancer with the drug-containing matrix.46. A method for producing a drug-containing lollipop for use intransmucosal delivery of the drug to a patient as defined in claim 15wherein the drug-containing matrix comprises from about 10 milligrams toabout 500 milligrams of methohexital.
 47. A method for producing adrug-containing lollipop for use in transmucosal delivery of the drug toa patient as defined in claim 26 wherein the drug-containing matrixcomprises from about 10 milligrams to about 500 milligrams ofmethohexital.
 48. A drug-containing lollipop for use in transmucosaldelivery of the drug to a patient as defined in claim 37 furthercomprising at least one flavoring.
 49. A drug-containing lollipop asdefined in claim 6 further comprising at least one flavoring dispersedwithin said integral mass.
 50. A drug-containing lollipop as defined inclaim 3 further comprising at least one releasing agent dispersed withinsaid integral mass.
 51. A drug-containing lollipop as defined in claim 6further comprising at least one flavor enhancer dispersed within saidintegral mass.
 52. A drug-containing lollipop as defined in claim 6further comprising at least one sweetener in addition to saidcarbohydrate material dispersed within said integral mass.